The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of PI3K-α enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with PI3K-α signaling with the compounds and compositions of the disclosure.

Description

83 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 17/921,580, filed on Oct. 26, 2022, which is a national stage of International (PCT) Patent Application No. PCT/US2021/029882, filed Apr. 29, 2021, which claims the benefit of U.S. Provisional Application No. 63/017,571, filed on Apr. 29, 2020, and U.S. Provisional Application No. 63/066,489, filed on Aug. 17, 2020; the entirety of each of which is hereby incorporated by reference.

›JOINT RESEARCH AGREEMENT

The present disclosure was made by or on behalf of the below listed parties to a joint research agreement. The joint research agreement was in effect on or before the date the present disclosure was made, and the present disclosure was made as a result of activities undertaken within the scope of the joint research agreement. The parties to the joint research agreement are 1) RELAY THERAPEUTICS, INC. and 2) D.E. SHAW RESEARCH, LLC.

›BACKGROUND

Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP 2 ) and phosphoinositol-3,4,5-triphosphate (PIP 3 ), which, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Of the two Class 1 PI3K sub-classes, Class 1 A PI3Ks are heterodimers composed of a catalytic p110 subunit (alpha, beta, or delta isoforms) constitutively associated with a regulatory subunit that can be p85 alpha, p55 alpha, p50 alpha, p85 beta, or p55 gamma. The Class 1B sub-class has one family member, a heterodimer composed of a catalytic p110 gamma subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class 1B PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)).

Consequently, the resultant phospholipid products of Class I PI3Ks link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). In many cases, PIP 2 and PIP 3 recruit Aid, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)).

Aberrant regulation of PI3K, which often increases survival through Aid activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring, and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110 alpha isoform, PIK3CA, and for Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85 alpha that serve to up-regulate the p85-p110 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et el., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that deregulation of phosphoinositol-3 kinase, and the upstream and downstream components of this signaling pathway, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).

In view of the above, inhibitors of PI3Kα would be of particular value in the treatment of proliferative disease and other disorders. While multiple inhibitors of PI3Ks have been developed (for example, taselisib, alpelisib, buparlisib and others), these molecules inhibit multiple Class 1A PI3K isoforms. Inhibitors that are active against multiple Class 1A PI3K isoforms are known as “pan-PI3K” inhibitors. A major hurdle for the clinical development of existing PI3K inhibitors has been the inability to achieve the required level of target inhibition in tumors while avoiding toxicity in cancer patients. Pan-PI3K inhibitors share certain target-related toxicities including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors is dependent on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, whereas inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, myelosuppression, and transaminitis (Hanker et al., Cancer Discovery (2019) PMID: 30837161. Therefore, selective inhibitors of PI3Kα may increase the therapeutic window, enabling sufficient target inhibition in the tumor while avoiding dose-limiting toxicity in cancer patients.

›SUMMARY

In some embodiments, the present disclosure provides a compound of formula I-1:

or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , Q, E, X, Y, and Z is as defined in embodiments and classes and subclasses herein.

In some embodiments, the present disclosure provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , Q, E, X, Y, and Z is as defined in embodiments and classes and subclasses herein.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treating a PI3Kα-mediated disorder comprising administering to a patient in need thereof a compound of formula 1, or composition comprising said compound.

In some embodiments, the present invention provides a process for providing a compound of formula 1, or synthetic intermediates thereof.

In some embodiments, the present invention provides a process for providing pharmaceutical compositions comprising compounds of formula I.

›DETAILED DESCRIPTION · 1 of 75

1. General Description of Certain Embodiments of the Invention

Compounds of the present invention, and pharmaceutical compositions thereof, are useful as inhibitors of PI3Kα. In some embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

E is —C(O)—, —C(R E ) 2 —, —C(R E ) 2 C(R E ) 2 —, —C(S)—, —S(O) 2 —, —OC(O)—, —N(R E )C(O)—, —C(O)N(R E )—, or —C(R E ) 2 C(O)—; Q is CH, C(R Q ), or N; X is CH, C(R X ), or N; Y is CH, C(R Y ), or N; Z is CH, C(R Z ), or N; R 1 is -L 1 -R 1A ; R 2 is -L 2 -R 2A ; each instance of R E is independently H or -L E -R EA . R Q is -L Q -R QA ; R X is -L X -R XA ; R Y is -L Y -R YA ; R Z is -L Z -R ZA ; or

two instances of R E are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of R EEC ; R Q and R 1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of R Q1C ; R Y and R Z are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of R YZC ;

each of L 1 , L 2 , L E , L Q , L X , L Y , and L Z is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(R L )—, —C(R L ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —N(R)—, —N(R)C(O)—, —N(R)C(NR)—, —N(R)C(NOR)—, —N(R)C(NCN)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) 2 —; R 1A is R A or R B substituted by r 1 instances of R 1C ; R 2A is R A or R B substituted by r 2 instances of R 2C ; R EA is R A or R B substituted by r 3 instances of R EC ; R QA is R A or R B substituted by r 4 instances of R QC ; R XA is R A or R B substituted by instances of R XC ; R YA is R A or R B substituted by r 6 instances of R VC ; R ZA is R A or R B substituted by r 7 instances of R ZC ; R L is R A or R B substituted by r 8 instances of R LC ; each instance of R A is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, or —B(OR) 2 ; each instance of R B is independently a C 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZC is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, —B(OR) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and

each of n, p, q, r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, or 4.

2. Compounds and Definitions

Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

›DETAILED DESCRIPTION · 2 of 75

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl”, unless otherwise indicated, as used herein, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C 1 -C 10 alkyl. Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

The term “lower alkyl” refers to a C 1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

As used herein, the term “C 1-8 (or C 1-6 , or C 1-4 ) bivalent saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH 2 ) n —, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl,” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.

The terms “heteroaryl” or “heteroaromatic”, unless otherwise defined, as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring. A heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.:

The terms “heterocyclyl” or “heterocyclic group”, unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings, and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen.

The term “partially unsaturated” in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. Where a partially unsaturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.:

›DETAILED DESCRIPTION · 3 of 75

The term “saturated” in the context of rings, unless otherwise defined, refers to a 3-10 membered monocyclic ring, or a 7-14 membered polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. Where a saturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.:

The terms “alkylene”, “arylene”, “cycloalkylene”, “heteroarylene”, “heterocycloalkylene”, and the other similar terms with the suffix “-ylene” as used herein refers to a divalently bonded version of the group that the suffix modifies. For example, “alkylene” is a divalent alkyl group connecting the groups to which it is attached.

As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.

Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH 2 ) 0-4 R ∘ ; —(CH 2 ) 0-4 OR ∘ ; —O(CH 2 ) 0-4 R ∘ , —O—(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 CH(OR ∘ ) 2 ; —(CH 2 ) 0-4 SR ∘ ; —(CH 2 ) 0-4 Ph, which may be substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R ∘ ; —CH═CHPh, which may be substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R ∘ ; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-4 N(R ∘ ) 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)R ∘ ; —N(R ∘ )C(S)R ∘ ; —(CH 2 ) 0-4 N(R ∘ )C(O)NR ∘ 2; —N(R ∘ )C(S)NR ∘ 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)OR ∘ ; —N(R ∘ )N(R ∘ )C(O)R ∘ ; —N(R ∘ )N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )N(R ∘ )C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)R ∘ ; —C(S)R ∘ ; —(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)SR ∘ ; —(CH 2 ) 0-4 C(O)OSiR ∘ 3; —(CH 2 ) 0-4 OC(O)R ∘ ; —OC(O)(CH 2 ) 0-4 SR ∘ ; —SC(S)SR ∘ ; —(CH 2 ) 0-4 SC(O)R ∘ ; —(CH 2 ) 0-4 C(O)NR ∘ 2; —C(S)NR ∘ 2 ; —C(S)SR ∘ ; —SC(S)SR ∘ , —(CH 2 ) 0-4 OC(O)NR ∘ 2 ; —C(O)N(OR ∘ )R ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(NOR ∘ )R ∘ ; —(CH 2 ) 0-4 SSR ∘ ; —(CH 2 ) 0-4 S(O) 2 R ∘ ; —(CH 2 ) 0-4 S(O) 2 OR ∘ ; —(CH 2 ) 0-4 OS(O) 2 R ∘ ; —S(O) 2 NR ∘ 2 ; —(CH 2 ) 0-4 S(O)R ∘ ; —N(R ∘ )S(O) 2 NR ∘ 2 ; —N(R ∘ )S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(NH)NR ∘ 2; —P(O)(OR ∘ )R ∘ ; —P(O)R ∘ 2 ; —OP(O)R ∘ 2 ; —OP(O)(OR ∘ ) 2 ; —SiR ∘ 3 ; —(C 1-4 straight or branched alkylene)O—N(R ∘ ) 2 ; or —(C 1-4 straight or branched alkylene)C(O)O—N(R ∘ ) 2 , wherein each R ∘ may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, —CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ∘ , taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R ∘ (or the ring formed by taking two independent occurrences of R ∘ together with their intervening atoms), are independently halogen, —(CH 2 ) 0-2 R • , -(haloR • ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR • , —(CH 2 ) 0-2 CH(OR • ) 2 ; —O(haloR • ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R • , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR*, —(CH 2 ) 0-2 SR • , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR • , —(CH 2 ) 0-2 NR • 2 , —NO 2 , —SiR • 3 , —OSiR • 3 , —C(O)SR • , —(C 1-4 straight or branched alkylene)C(O)OR • , or —SSR • wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ∘ include ═O and ═S.

›DETAILED DESCRIPTION · 4 of 75

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR* 2 , ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) 2 R*, ═NR*, ═NOR*, —O(C(R* 2 )) 23 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R • , -(haloR • ), —OH, —OR • , —O(haloR • ), —CN, —C(O)OH, —C(O)OR • , —NH 2 , —NHR • , —NR • 2 , or —NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R † , —NR † 2 , —C(O)R † , —C(O)OR † , —C(O)C(O)R † , —C(O)CH 2 C(O)R † , —S(O) 2 R † , —S(O) 2 NR † 2 , —C(S)NR † 2 , —C(NH)NR † 2 , or —N(RT)S(O) 2 R † ; wherein each R † is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R † , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R † are independently halogen, —R • , -(haloR • ), —OH, —OR • , —O(haloR • ), —CN, —C(O)OH, —C(O)OR • , —NH 2 , —NHR • , —NR • 2 , or —NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term “isomer” as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term “stereoisomer” as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are within the scope of the invention.

The term “tautomer” as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the invention are within the scope of the invention.

The term “isotopic substitution” as used herein refers to the substitution of an atom with its isotope. The term “isotope” as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen. Examples of the isotope of a hydrogen atom include 2 H (also represented as D) and 3 H. Examples of the isotope of a carbon atom include 13 C and 14 C. Examples of the isotope of an oxygen atom include 18 O. Unless otherwise stated, all isotopic substitution of the compounds of the invention are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, for example, a warhead moiety, R W , of a provided compound comprises one or more deuterium atoms.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. ( J. Pharm. Sci. 1977, 66(1), 1; and Gould, P. L., Int. J. Pharmaceutics 1986, 33, 201-217; (each hereby incorporated by reference in its entirety).

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

›DETAILED DESCRIPTION · 5 of 75

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to PI3Kα signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to PI3Kα signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

The phrase “in need thereof” refers to the need for symptomatic or asymptomatic relief from conditions related to PI3Kα signaling activity or that may otherwise be relieved by the compounds and/or compositions of the disclosure.

3. Description of Exemplary Embodiments

As described above, in some embodiments, the present invention provides a compound of formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

each of L 1 , L 2 , L E , L Q , L X , L Y , and L Z is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(R L )—, —C(R L ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —N(R)—, —N(R)C(O)—, —N(R)C(NR)—, —N(R)C(NOR)—, —N(R)C(NCN)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) 2 —; R 1A is R A or R B substituted by r instances of R 1C ; R 2A is R A or R B substituted by r 2 instances of R 2C ; R EA is R A or R B substituted by r 3 instances of R EC ; R QA is R A or R B substituted by r 4 instances of R QC ; R XA is R A or R B substituted by r 5 instances of R XC ; R YA is R A or R B substituted by r 6 instances of R YC ; R ZA is R A or R B substituted by r instances of R ZC ; R L is R A or R B substituted by r 8 instances of R LC ; each instance of R A is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —S(O)(NCN)R, —S(NCN)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, or —B(OR) 2 ; each instance of R B is independently a C 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C and R YZC is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, —B(OR) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

›DETAILED DESCRIPTION · 6 of 75

In some embodiments, the present invention provides a compound of Formula I-1, wherein each of E, Q, X Y, Z, R 1 , R 2 , R E , R Q , R X , R Y , R Z , R 1A , R 2A , R EA , R QA , R XA , R YA , R ZA R L , R A , R B , R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , R YZC , R, n, p q r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is as defined below, and described in embodiments herein, both singly and in combination.

In certain embodiments, R YA is —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —S(O)(NCN)R, or —S(NCN)R. In certain embodiments, R YA is —S(O)(NR)R, —S(O)(NCN)R, or —S(NCN)R. In certain embodiments, R YA is —S(O)(NCN)R or —S(NCN)R. In certain embodiments, R YA is —S(O)(NCN)R. In certain embodiments, R YA is —S(NCN)R. In some embodiments, R YA is selected from the groups depicted in the compounds in Table 1.

In certain embodiments, R A is —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —S(O)(NCN)R, or —S(NCN)R. In certain embodiments, R A is —S(O)(NR)R, —S(O)(NCN)R, or —S(NCN)R. In certain embodiments, R A is —S(O)(NCN)R or —S(NCN)R. In certain embodiments, R A is —S(O)(NCN)R. In certain embodiments, R A is —S(NCN)R. In some embodiments, R A is selected from the groups depicted in the compounds in Table 1.

In certain embodiments, n is 1, 2, 3, 4, or 5. In certain embodiments, n is 2, 3, 4, or 5. In certain embodiments, n is 3, 4, or 5. In certain embodiments, n is 4 or 5. In certain embodiments, n is 5. In certain embodiments, n is selected from the values represented in the compounds in Table 1.

In certain embodiments, p is 1, 2, 3, 4, or 5. In certain embodiments, p is 2, 3, 4, or 5. In certain embodiments, p is 3, 4, or 5. In certain embodiments, p is 4 or 5. In certain embodiments, p is 5. In certain embodiments, p is selected from the values represented in the compounds in Table 1.

In certain embodiments, q is 1, 2, 3, 4, or 5. In certain embodiments, q is 2, 3, 4, or 5. In certain embodiments, q is 3, 4, or 5. In certain embodiments, q is 4 or 5. In certain embodiments, q is 5. In certain embodiments, q is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 1 is 1, 2, 3, 4, or 5. In certain embodiments, r 1 is 2, 3, 4, or 5. In certain embodiments, r 1 is 3, 4, or 5. In certain embodiments, r 1 is 4 or 5. In certain embodiments, r 1 is 5. In certain embodiments, r 1 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 2 is 1, 2, 3, 4, or 5. In certain embodiments, r 2 is 2, 3, 4, or 5. In certain embodiments, r 2 is 3, 4, or 5. In certain embodiments, r 2 is 4 or 5. In certain embodiments, r 2 is 5. In certain embodiments, r 2 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 3 is 1, 2, 3, 4, or 5. In certain embodiments, r 3 is 2, 3, 4, or 5. In certain embodiments, r 3 is 3, 4, or 5. In certain embodiments, r 3 is 4 or 5. In certain embodiments, r 3 is 5. In certain embodiments, r 3 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 4 is 1, 2, 3, 4, or 5. In certain embodiments, r 4 is 2, 3, 4, or 5. In certain embodiments, r 4 is 3, 4, or 5. In certain embodiments, r 4 is 4 or 5. In certain embodiments, r 4 is 5. In certain embodiments, r 4 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 5 is 1, 2, 3, 4, or 5. In certain embodiments, r 5 is 2, 3, 4, or 5. In certain embodiments, r 5 is 3, 4, or 5. In certain embodiments, r 5 is 4 or 5. In certain embodiments, r 5 is 5. In certain embodiments, r 5 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 6 is 1, 2, 3, 4, or 5. In certain embodiments, r 6 is 2, 3, 4, or 5. In certain embodiments, r 6 is 3, 4, or 5. In certain embodiments, r 6 is 4 or 5. In certain embodiments, r 6 is 5. In certain embodiments, r 6 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 7 is 1, 2, 3, 4, or 5. In certain embodiments, r 7 is 2, 3, 4, or 5. In certain embodiments, r 7 is 3, 4, or 5. In certain embodiments, r 7 is 4 or 5. In certain embodiments, r 7 is 5. In certain embodiments, r 7 is selected from the values represented in the compounds in Table 1.

In certain embodiments, r 8 is 1, 2, 3, 4, or 5. In certain embodiments, r 8 is 2, 3, 4, or 5. In certain embodiments, r 8 is 3, 4, or 5. In certain embodiments, r 8 is 4 or 5. In certain embodiments, r 8 is 5. In certain embodiments, r 8 is selected from the values represented in the compounds in Table 1.

As described above, in some embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

›DETAILED DESCRIPTION · 7 of 75

each of L 1 , L 2 , L E , L Q , L X , L Y , and L Z is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(R L )—, —C(R E ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —N(R)—, —N(R)C(O)—, —N(R)C(NR)—, —N(R)C(NOR)—, —N(R)C(NCN)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) 2 —; R 1A is R A or R B substituted by r 1 instances of R 1C ; R 2A is R A or R B substituted by r 2 instances of R 2C ; R EA is R A or R B substituted by r 3 instances of R EC ; R QA is R A or R B substituted by r 4 instances of R QC ; R XA is R A or R B substituted by instances of R XC ; R YA is R A or R B substituted by r 6 instances of R YC ; R ZA is R A or R B substituted by r instances of R ZC ; R L is R A or R B substituted by r 8 instances of R LC ; each instance of R A is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, or —B(OR) 2 ; each instance of R B is independently a C 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZC is independently oxo, deuterium, halogen, —CN, —NO 2 , —OR, —SF 5 , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O) 2 F, —S(O)R, —S(O)NR 2 , —S(O)(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —P(O)R 2 , —P(O)(R)OR, —B(OR) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

each of n, p, q, r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, or 4.

As defined generally above, E is —C(O)—, —C(R E ) 2 —, —C(R E ) 2 C(R E ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —C(S)—, —S(O) 2 —, —OC(O)—, —N(R E )C(O)—, —C(O)N(R E )—, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(O)—. In some embodiments, E is —OC(O)— or —N(R E )C(O)—. In some embodiments, E is —C(R E ) 2 —, C 3-6 cycloalkylene, or C 3-6 heterocycloalkylene.

In some embodiments, E is —C(O)—, —OC(O)—, —N(R E )C(O)—, or —C(R E ) 2 C(O)—. In some embodiments, E is —OC(O)—, —N(R E )C(O)—, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(O)— or —N(R E )C(O)—.

In some embodiments, E is —C(O)—, —C(R E ) 2 —, —C(S)—, or —S(O) 2 —. In some embodiments, E is —C(O)—, —C(R E ) 2 —, or —C(S)—. In some embodiments, E is —C(O)— or —C(S)—.

In some embodiments, E is —C(R E ) 2 C(R E ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —OC(O)—, —N(R E )C(O)—, —C(O)N(R E )—, or —C(R E ) 2 C(O)—. In some embodiments, E is C 3-6 cycloalkylene or C 3-6 heterocycloalkylene. In some embodiments, E is —C(R E ) 2 C(R E ) 2 —, —OC(O)—, —N(R E )C(O)—, —C(O)N(R E )—, or —C(R E ) 2 C(O)—. In some embodiments, E is —OC(O)—, —N(R E )C(O)—, —C(O)N(R E )—, or —C(R E ) 2 C(O)—. In some embodiments, E is —OC(O)—, —N(R E )C(O)—, or —C(O)N(R E )—. In some embodiments, E is —N(R E )C(O)— or —C(O)N(R E )—. In some embodiments, E is —N(H)C(O)— or —C(O)N(H)—. In some embodiments, E is —N(CH 3 )C(O)— or —C(O)N(CH 3 )—.

In some embodiments, E is —S(O) 2 —, —OC(O)—, —N(R E )C(O)—, or —C(O)N(R E )—. In some embodiments, E is —C(O)—, —C(R E ) 2 —, —C(R E ) 2 C(R E ) 2 —, C 3-6 cycloalkylene, C 3-6 heterocycloalkylene, —C(S)—, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(O)—, —C(R E ) 2 —, —C(R E ) 2 C(R E ) 2 —, —C(S)—, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(O)—, —C(S)—, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(R E ) 2 —, —C(R E ) 2 C(R E ) 2 —, or —C(R E ) 2 C(O)—. In some embodiments, E is —C(R E ) 2 — or —C(R E ) 2 C(R E ) 2 —.

In some embodiments, E is —C(R E ) 2 —. In some embodiments, E is —C(R E ) 2 C(R E ) 2 —. In some embodiments, E is C 3-6 cycloalkylene. In some embodiments, E is C 3-6 heterocycloalkylene. In some embodiments, E is —C(S)—. In some embodiments, E is —S(O) 2 —. In some embodiments, E is —OC(O)—. In some embodiments, E is —N(R E )C(O)—. In some embodiments, E is —N(H)C(O)—. In some embodiments, E is —N(CH 3 )C(O)—. In some embodiments, E is —C(O)N(R E )—. In some embodiments, E is —C(O)N(H)—. In some embodiments, E is —C(O)N(CH 3 )—. In some embodiments, E is —C(R E ) 2 C(O)—.

›DETAILED DESCRIPTION · 8 of 75

In some embodiments, E is selected from the groups depicted in the compounds in Table 1.

As defined generally above, Q is CH, C(R Q ), or N. In some embodiments, Q is CH. In some embodiments, Q is C(R Q ). In some embodiments, Q is N. In some embodiments, Q is CH or C(R Q ). In some embodiments, Q is CH or N. In some embodiments, Q is C(R Q ) or N. In some embodiments, Q is selected from the groups depicted in the compounds in Table 1.

As defined generally above, X is CH, C(R X ), or N. In some embodiments, X is CH. In some embodiments, X is C(R X ). In some embodiments, X is N. In some embodiments, X is CH or C(R X ). In some embodiments, X is CH or N. In some embodiments, X is C(R X ) or N. In some embodiments, X is selected from the groups depicted in the compounds in Table 1.

As defined generally above, Y is CH, C(R Y ), or N. In some embodiments, Y is CH. In some embodiments, Y is C(R Y ). In some embodiments, Y is N. In some embodiments, Y is CH or C(R Y ). In some embodiments, Y is CH or N. In some embodiments, Y is C(R Y ) or N. In some embodiments, Y is selected from the groups depicted in the compounds in Table 1.

As defined generally above, Z is CH, C(R Z ), or N. In some embodiments, Z is CH. In some embodiments, Z is C(R Z ). In some embodiments, Z is N. In some embodiments, Z is CH or C(R Z ). In some embodiments, Z is CH or N. In some embodiments, Z is C(R Z ) or N. In some embodiments, Z is selected from the groups depicted in the compounds in Table 1.

As defined generally above, R 1 is -L 1 -R 1A or R Q and R 1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of R Q1C . In some embodiments, R 1 is -L 1 -R 1A . In some embodiments, R 1 is —R 1A .

In some embodiments, R Q and R 1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of R Q1C In some embodiments, R Q and R 1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with p instances of R Q1C . In some embodiments, R Q and R 1 are taken together with their intervening atoms to form an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with p instances of R Q1C .

In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein R 1C embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein R 1C is as defined in the embodiments and classes and subclasses herein. In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein R 1C is as defined in the embodiments and classes and subclasses herein.

In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein each instance of R 1C is independently halogen, —CN, —O-(optionally substituted C 1-6 aliphatic), or an optionally substituted C 1-6 aliphatic. In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein each instance of R 1C is independently fluorine, chlorine, —CH 3 , —CHF 2 , or —CF 3 . In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein R 1C is halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.

In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

wherein R 1C and r 1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

In some embodiments, R 1 (i.e. -L 1 -R 1A taken together) is

In some embodiments, R 1 (i.e. -L-R 1A taken together) is

In some embodiments, R 1 is selected from the groups depicted in the compounds in Table 1.

As defined generally above, R 2 is -L 2 -R 2A . In some embodiments, R 2 (i.e. -L 2 -R 2A taken together) is —N(R)C(O)—R 2A or —R 2A , wherein R and R 2A are as defined in the embodiments and classes and subclasses herein. In some embodiments, R 2 (i.e. -L 2 -R 2A taken together) is —N(R)C(O)—R 2A , wherein R and R 2A are as defined in the embodiments and classes and subclasses herein. In some embodiments, R 2 (i.e. -L 2 -R 2A taken together) is —N(H)C(O)—R 2A , wherein R 2A is as defined in the embodiments and classes and subclasses herein. In some embodiments, R 2 (i.e. -L 2 -R 2A taken together) is —N(H)C(O)—R 2A , wherein R 2A is R B substituted by r 2 instances of R 2C . In some embodiments, R 2 is -R 2A .

In some embodiments, R 2 is —N(H)C(O)—R 2A , —N(H)C(O)N(H)—R 2A , —C(O)N(H)—R 2A , —N(H)—R 2A , —S(O) 2 CH 2 —R 2A , —CH 2 S(O) 2 —R 2A , or —C(H)(CH 3 )OH. In some embodiments, R 2 is —N(H)C(O)—R 2A , —N(H)C(O)N(H)—R 2A , or —N(H)—R 2A . In some embodiments, R 2 is —C(O)N(H)—R 2A , —CH 2 S(O) 2 —R 2A , or —C(H)(CH 3 )OH. In some embodiments, R 2 is —S(O) 2 CH 2 —R 2A or —CH 2 S(O) 2 —R 2A .

›DETAILED DESCRIPTION · 9 of 75

In some embodiments, R 2 is —N(H)C(O)N(H)—R 2A . In some embodiments, R 2 is —C(O)N(H)—R 2A . In some embodiments, R 2 is —N(H)—R 2A . In some embodiments, R 2 is —S(O) 2 CH 2 —R 2A . In some embodiments, R 2 is —CH 2 S(O) 2 —R 2A . In some embodiments, R 2 is —C(H)(CH 3 )OH.